PEAK: Panitumumab Plus mFOLFOX6 vs. Bevacizumab Plus mFOLFOX6 for First Line Treatment of Metastatic Colorectal Cancer (mCRC) Patients With Wild-Type Kirsten Rat Sarcoma-2 Virus (KRAS) Tumors

Colorectal Cancer Clinical Trial

Official title:

A Randomized, Multicenter, Phase 2 Study to Compare the Efficacy of Panitumumab in Combination With mFOLFOX6 to the Efficacy of Bevacizumab in Combination With mFOLFOX6 in Patients With Previously Untreated, KRAS Wild-Type, Unresectable, Metastatic Colorectal Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00819780
• Other study ID #: 20070509
• Status: Completed
• Phase: Phase 2
• Start date: April 24, 2009
• Est. completion date: July 7, 2016

Study information

• Verified date: November 2022
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of this study is to estimate the treatment effect on progression-free survival (PFS) of panitumumab relative to bevacizumab in combination with mFOLFOX6 chemotherapy as first-line therapy in patients with tumors expressing wild-type KRAS, unresectable mCRC.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 285
• Est. completion date: July 7, 2016
• Est. primary completion date: May 30, 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically or cytologically-confirmed adenocarcinoma of the colon or rectum in patients with unresectable metastatic (M1) disease
• Patients with at least 1 uni-dimensionally measurable lesion of at least 10 mm per modified Response Evaluation Criteria in Solid Tumors (RECIST) guidelines
• Wild-type KRAS tumor status confirmed by an Amgen approved central laboratory or an experienced laboratory (local laboratory) per local regulatory guidelines using a validated test method
• Eastern Cooperative Oncology Group (ECOG) score of 0 or 1
• Men or women 18 years of age or older
• Adequate hematologic, renal, hepatic, metabolic, and coagulation function

Exclusion Criteria:

• History of prior or concurrent central nervous system (CNS) metastases
• Prior chemotherapy or other systemic anticancer therapy for treatment of metastatic colorectal carcinoma
• Clinically significant cardiac disease
• Clinically significant peripheral sensory neuropathy
• Active inflammatory bowel disease
• Recent gastroduodenal ulcer to be active or uncontrolled
• History of interstitial lung disease
• Recent pulmonary embolism, deep vein thrombosis, or other significant venous event
• Pre-existing bleeding diathesis and/or coagulopathy with exception of well-controlled anticoagulation therapy
• Recent major surgical procedure, open biopsy, or significant traumatic injury not yet recovered from prior major surgery.

Related Conditions & MeSH terms

• Colon Cancer
• Colonic Neoplasms
• Colorectal Cancer
• Colorectal Neoplasms
• Metastatic Colorectal Cancer
• Rectal Cancer
• Rectal Neoplasms

Intervention

Drug:
• Panitumumab
Panitumumab is a fully human immunoglobulin G (IgG)2 monoclonal antibody antagonist directed against human Epidermal Growth Factor receptor (EGFr).
• Bevacizumab
Bevacizumab is a humanized monoclonal IgG1 antibody that is directed against Vascular Endothelial Growth Factor (VEGF).
• mFOLFOX6
mFOLFOX6 regimen is a combination therapy of oxaliplatin (85 mg/m^2) administered as a 2-hour infusion on Day 1; leucovorin (400 mg/m^2) administered as a 2-hour infusion on Day 1; followed by a loading dose of 5-fluorouracil (5-FU; 400 mg/m^2) IV bolus administered over approximately 2 to 4 minutes on Day 1, then 5- FU (2400 mg/m^2) via ambulatory pump administered for a period of 46 to 48 hours.

Locations

Country	Name	City	State
Belgium	Research Site	Charleroi
Belgium	Research Site	Edegem
Belgium	Research Site	Libramont
Belgium	Research Site	Sint-Niklaas
Canada	Research Site	Calgary	Alberta
Canada	Research Site	Edmonton	Alberta
Canada	Research Site	Greenfield Park	Quebec
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Oshawa	Ontario
Canada	Research Site	Quebec
Canada	Research Site	Vancouver	British Columbia
Canada	Research Site	Victoria	British Columbia
Germany	Research Site	Berlin
Germany	Research Site	Bielefeld
Germany	Research Site	München
Germany	Research Site	München
Germany	Research Site	Magdeburg
Germany	Research Site	Passau
Germany	Research Site	Regensburg
Germany	Research Site	Würzburg
Italy	Research Site	Alba (CN)
Italy	Research Site	Fano
Italy	Research Site	Genova
Italy	Research Site	Mantova
Italy	Research Site	Udine
Italy	Research Site	Varese
Spain	Research Site	A Coruña	Galicia
Spain	Research Site	Elche	Comunidad
Spain	Research Site	Málaga	AndalucÃ-a
Spain	Research Site	Sabadell	Cataluña
Spain	Research Site	San Sebastián De Los Reyes	Madrid
Spain	Research Site	Santander	Cantabria
United States	Research Site	Akron	Ohio
United States	Research Site	Albuquerque	New Mexico
United States	Research Site	Alpharetta	Georgia
United States	Research Site	Augusta	Georgia
United States	Research Site	Austin	Texas
United States	Research Site	Baltimore	Maryland
United States	Research Site	Berkeley	California
United States	Research Site	Bethesda	Maryland
United States	Research Site	Beverly Hills	California
United States	Research Site	Birmingham	Alabama
United States	Research Site	Boston	Massachusetts
United States	Research Site	Boynton Beach	Florida
United States	Research Site	Buffalo	New York
United States	Research Site	Burbank	California
United States	Research Site	Chesapeake	Virginia
United States	Research Site	Columbus	Ohio
United States	Research Site	Coral Springs	Florida
United States	Research Site	Corpus Christi	Texas
United States	Research Site	Dallas	Texas
United States	Research Site	Danville	Kentucky
United States	Research Site	Daytona Beach	Florida
United States	Research Site	Denver	Colorado
United States	Research Site	East Setauket	New York
United States	Research Site	Fountain Valley	California
United States	Research Site	Greenville	South Carolina
United States	Research Site	Gurnee	Illinois
United States	Research Site	Hazard	Kentucky
United States	Research Site	Hershey	Pennsylvania
United States	Research Site	Hollywood	Florida
United States	Research Site	Huntersville	North Carolina
United States	Research Site	Huntsville	Alabama
United States	Research Site	Indianapolis	Indiana
United States	Research Site	Kalamazoo	Michigan
United States	Research Site	La Verne	California
United States	Research Site	Lake Worth	Florida
United States	Research Site	Lambertville	Michigan
United States	Research Site	Lansing	Michigan
United States	Research Site	Memphis	Tennessee
United States	Research Site	Mount Pleasant	South Carolina
United States	Research Site	Mountain Lakes	New Jersey
United States	Research Site	Newport News	Virginia
United States	Research Site	Newport News	Virginia
United States	Research Site	Orange	California
United States	Research Site	Overland Park	Kansas
United States	Research Site	Paducah	Kentucky
United States	Research Site	Peoria	Illinois
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Post Falls	Idaho
United States	Research Site	Raleigh	North Carolina
United States	Research Site	Riverside	California
United States	Research Site	Roseville	California
United States	Research Site	Round Rock	Texas
United States	Research Site	Savannah	Georgia
United States	Research Site	Sparta	New Jersey
United States	Research Site	Spokane	Washington
United States	Research Site	Stamford	Connecticut
United States	Research Site	Staten Island	New York
United States	Research Site	Temple	Texas
United States	Research Site	Tyler	Texas
United States	Research Site	Vancouver	Washington
United States	Research Site	Waterbury	Connecticut
United States	Research Site	White River Junction	Vermont
United States	Research Site	Wichita	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Germany,  Italy,  Spain, 

References & Publications (11)

Boeckx N, Koukakis R, Op de Beeck K, Rolfo C, Van Camp G, Siena S, Tabernero J, Douillard JY, Andre T, Peeters M. Effect of Primary Tumor Location on Second- or Later-line Treatment Outcomes in Patients With RAS Wild-type Metastatic Colorectal Cancer and All Treatment Lines in Patients With RAS Mutations in Four Randomized Panitumumab Studies. Clin Colorectal Cancer. 2018 Sep;17(3):170-178.e3. doi: 10.1016/j.clcc.2018.03.005. Epub 2018 Mar 8. — View Citation

Boeckx N, Koukakis R, Op de Beeck K, Rolfo C, Van Camp G, Siena S, Tabernero J, Douillard JY, Andre T, Peeters M. Primary tumor sidedness has an impact on prognosis and treatment outcome in metastatic colorectal cancer: results from two randomized first-line panitumumab studies. Ann Oncol. 2017 Aug 1;28(8):1862-1868. doi: 10.1093/annonc/mdx119. — View Citation

Heinemann V, Rivera F, O'Neil BH, Stintzing S, Koukakis R, Terwey JH, Douillard JY. A study-level meta-analysis of efficacy data from head-to-head first-line trials of epidermal growth factor receptor inhibitors versus bevacizumab in patients with RAS wild-type metastatic colorectal cancer. Eur J Cancer. 2016 Nov;67:11-20. doi: 10.1016/j.ejca.2016.07.019. Epub 2016 Sep 1. — View Citation

Modest DP, Rivera F, Bachet JB, de Braud F, Pietrantonio F, Koukakis R, Demonty G, Douillard JY. Panitumumab-based maintenance after oxaliplatin discontinuation in metastatic colorectal cancer: A retrospective analysis of two randomised trials. Int J Cancer. 2019 Jul 15;145(2):576-585. doi: 10.1002/ijc.32110. Epub 2019 Jan 24. — View Citation

Peeters M, Forget F, Karthaus M, Valladares-Ayerbes M, Zaniboni A, Demonty G, Guan X, Rivera F. Exploratory pooled analysis evaluating the effect of sequence of biological therapies on overall survival in patients with RAS wild-type metastatic colorectal carcinoma. ESMO Open. 2018 Feb 24;3(2):e000297. doi: 10.1136/esmoopen-2017-000297. eCollection 2018. — View Citation

Peeters M, Price T, Taieb J, Geissler M, Rivera F, Canon JL, Pentheroudakis G, Koukakis R, Burdon P, Siena S. Relationships between tumour response and primary tumour location, and predictors of long-term survival, in patients with RAS wild-type metastatic colorectal cancer receiving first-line panitumumab therapy: retrospective analyses of the PRIME and PEAK clinical trials. Br J Cancer. 2018 Aug;119(3):303-312. doi: 10.1038/s41416-018-0165-z. Epub 2018 Jul 17. — View Citation

Rivera F, Karthaus M, Hecht JR, Sevilla I, Forget F, Fasola G, Canon JL, Guan X, Demonty G, Schwartzberg LS. Final analysis of the randomised PEAK trial: overall survival and tumour responses during first-line treatment with mFOLFOX6 plus either panitumumab or bevacizumab in patients with metastatic colorectal carcinoma. Int J Colorectal Dis. 2017 Aug;32(8):1179-1190. doi: 10.1007/s00384-017-2800-1. Epub 2017 Apr 19. — View Citation

Sartore-Bianchi A, Garcia-Alfonso P, Geissler M, Kohne CH, Peeters M, Price T, Valladares-Ayerbes M, Zhang Y, Burdon P, Taieb J, Modest DP. Relationships Between Kohne Category/Baseline Tumor Load and Early Tumor Shrinkage, Depth of Response, and Outcomes in Metastatic Colorectal Cancer. Clin Colorectal Cancer. 2021 Dec;20(4):305-313. doi: 10.1016/j.clcc.2021.05.007. Epub 2021 May 25. — View Citation

Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, Yu H, Oliner KS, Go WY. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014 Jul 20;32(21):2240-7. doi: 10.1200/JCO.2013.53.2473. Epub 2014 Mar 31. — View Citation

Taieb J, Geissler M, Rivera F, Karthaus M, Wilson R, Loupakis F, Price T, Tracy M, Burdon P, Peeters M. Relationship Between Tumor Response and Tumor-Related Symptoms in RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses From 3 Panitumumab Trials. Clin Colorectal Cancer. 2019 Dec;18(4):245-256.e5. doi: 10.1016/j.clcc.2019.07.009. Epub 2019 Jul 29. — View Citation

Taieb J, Rivera F, Siena S, Karthaus M, Valladares-Ayerbes M, Gallego J, Geissler M, Koukakis R, Demonty G, Peeters M. Exploratory analyses assessing the impact of early tumour shrinkage and depth of response on survival outcomes in patients with RAS wild-type metastatic colorectal cancer receiving treatment in three randomised panitumumab trials. J Cancer Res Clin Oncol. 2018 Feb;144(2):321-335. doi: 10.1007/s00432-017-2534-z. Epub 2017 Oct 28. Erratum In: J Cancer Res Clin Oncol. 2018 Feb 15;: — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS)	PFS was defined as the time from the date of randomization to the date of first disease progression, or death within 60 days after the last evaluable tumor assessment or randomization date (whichever was later). Participants not meeting the criteria by the cutoff date were censored at the last evaluable tumor assessment date. Tumor response was evaluated by the investigator per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 every 8 weeks until radiographic disease progression. Progression is defined as at least a 20% increase in the size of target lesions, unequivocal progression of existing non-target lesions, or any new lesions.	From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks.
Secondary	Overall Survival	Overall survival was defined as the time from randomization to the date of death, with participants alive or lost to follow-up at the analysis data cutoff date censored at their last contact date.	From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks.
Secondary	Percentage of Participants With an Objective Response	Objective response was defined as having a confirmed complete response (CR) or partial response (PR) during first-line treatment, based on the investigator's review of scans using a modified-RECIST v1.0. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. Complete Response: Disappearance of all target and non-target lesions and no new lesions. Partial Response: At least a 30% decrease in the sum of the longest diameter (SLD) of target lesions and no progression of non-target lesions and no new lesions, or the disappearance of all target lesions with persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease and no new lesions.	From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks.
Secondary	Duration of Response	For participants with a confirmed objective response, the time from first confirmed objective response to radiologic disease progression per modified RECIST 1.0 criteria or death. For participants who responded and have not progressed or died, duration of response was censored at their last evaluable disease assessment date.	From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks.
Secondary	Time to Disease Progression	Time to progression (TTP) is defined as the time from randomization to the date of radiologic disease progression per modified RECIST 1.0 criteria. Participants not meeting criteria for disease progression by the analysis data cutoff date were censored at their last evaluable disease assessment date. Progression is defined as at least a 20% increase in the size of target lesions, unequivocal progression of existing non-target lesions, or any new lesions.	From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks.
Secondary	Time to Initial Objective Response	For participants with a confirmed objective response, the time from randomization to the date of first confirmed objective response. Assessments are based on the investigator's review of scans using a modified-RECIST v1.0. An objective response is defined as a best tumor response of complete or partial response. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met.	From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks.
Secondary	Resection Rate	The resection rate was defined as the percentage of participants with a surgical procedure that resulted in partial reduction or complete eradication of all metastatic disease.	From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks.
Secondary	Progression-free Survival (PFS) in Participants With Wild-type Rat Sarcoma Viral Oncogene Homolog (RAS)	PFS was defined as the time from the date of randomization to the date of first disease progression, or death within 60 days after the last evaluable tumor assessment or randomization date (whichever was later). Participants not meeting the criteria by the cutoff date were censored at the last evaluable tumor assessment date. Tumor response was evaluated by the investigator per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 every 8 weeks until radiographic disease progression. Progression is defined as at least a 20% increase in the size of target lesions, unequivocal progression of existing non-target lesions, or any new lesions.	From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks.
Secondary	Progression-free Survival (PFS) in Participants With Wild-type RAS / V-raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF)	PFS was defined as the time from the date of randomization to the date of first disease progression, or death within 60 days after the last evaluable tumor assessment or randomization date (whichever was later). Participants not meeting the criteria by the cutoff date were censored at the last evaluable tumor assessment date. Tumor response was evaluated by the investigator per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 every 8 weeks until radiographic disease progression. Progression is defined as at least a 20% increase in the size of target lesions, unequivocal progression of existing non-target lesions, or any new lesions.	From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks.
Secondary	Overall Survival in Participants With Wild-type RAS	Overall survival was defined as the time from randomization to the date of death, with participants alive or lost to follow-up at the analysis data cutoff date censored at their last contact date.	From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks.
Secondary	Overall Survival in Participants With Wild-type RAS / BRAF	Overall survival was defined as the time from randomization to the date of death, with participants alive or lost to follow-up at the analysis data cutoff date censored at their last contact date.	From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks.
Secondary	Percentage of Participants With an Objective Response for Participants With Wild-type RAS	Objective response was defined as having a confirmed complete response (CR) or partial response (PR) during first-line treatment, based on the investigator's review of scans using a modified-RECIST v1.0. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met.; Complete Response: Disappearance of all target and non-target lesions and no new lesions. Partial Response: At least a 30% decrease in the sum of the longest diameter (SLD) of target lesions and no progression of non-target lesions and no new lesions, or the disappearance of all target lesions with persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease and no new lesions.	From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks.
Secondary	Percentage of Participants With an Objective Response for Participants With Wild-type RAS / BRAF	Objective response was defined as having a confirmed complete response (CR) or partial response (PR) during first-line treatment, based on the investigator's review of scans using a modified-RECIST v1.0. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. Complete Response: Disappearance of all target and non-target lesions and no new lesions. Partial Response: At least a 30% decrease in the sum of the longest diameter (SLD) of target lesions and no progression of non-target lesions and no new lesions, or the disappearance of all target lesions with persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease and no new lesions.	From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks.
Secondary	Number of Participants With Adverse Events (AEs)	Severity was graded using Common Terminology Criteria for Adverse Events (CTCAE) v3.0, with the exception of some dermatology/skin adverse events that were graded using CTCAE v3.0 with modifications. Fatal adverse events are classified as grade 5. Serious adverse events include any event that is fatal, life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or other significant medical hazard. Treatment-related AEs were those that the investigator considered a reasonable possibility that might have been caused by study drug.	The time frame for adverse event reporting is from the first dose date to 30 days since the last dose date. The median time frame is 8.0 months for Panitumumab Plus mFOLFOX arm and 7.3 months for Bevacizumab Plus mFOLFOX6 arm.

External Links

•   AmgenTrials clinical trials website